Pharmaceutical formulations: salts of 8-[1-3,5-bis-(trifluoromethyl)phenyl)-ethoxy-methyl]-8-phenyl-1,7-diaza-spiro[4.5]decan-2-one and treatment methods using the same

ABSTRACT

Pharmaceutical formulations containing salts of (5S,8S)-8-[{(1R)-1-(3,5-Bis-(trifluoromethyl)phenyl]-ethoxy}-methyl]-8-phenyl-1,7-diazaspiro[4.5]decan-2-one, represented by Formula I, are disclosed. Disclosed also are methods of treatment utilizing such dosage forms.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a continuation of U.S. application Ser. No.13/184,926, filed Jul. 18, 2011, now issued as U.S. Pat. No. 8,404,702;which is a continuation of U.S. application Ser. No. 12/487,263, filedJun. 18, 2009, issued as U.S. Pat. No. 7,981,905; which is a division ofU.S. application Ser. No. 11/732,663, filed on Apr. 4, 2007, now issuedas U.S. Pat. No. 7,563,801; which claims priority from U.S. ProvisionalApplication 60/789,514, filed on Apr. 5, 2006.

FIELD OF THE INVENTION

This application generally relates to pharmaceutically usefulformulations comprising salts of8-[{1-(3,5-Bis-(trifluoromethyl)phenyl)-ethoxy}methyl]-8-phenyl-1,7-diaza-spiro[4.5]decan-2-oneand treatment methods employing the same.

BACKGROUND OF THE INVENTION

The preparation of diazaspirodecan-2-ones named (in accordance withBielstein nomenclature)8-[{1-(3,5-Bis-(trifluoromethyl)phenyl)-ethoxy}methyl]-8-phenyl-1,7-diazaspiro[4.5]decan-2-one,for example,(5S,8S)-8-[{(1R)-1-(3,5-Bis-(trifluoromethyl)phenyl)-ethoxy}methyl]-8-phenyl-1,7-diazaspiro[4.5]decan-2-one(the compound of Formula I) is disclosed in published U.S. Pat. No.7,049,320 issued May 23, 2006 (the '320 patent), which is incorporatedherein by reference in its entirety.

The compounds disclosed in the '320 patent are classified as Tachykinincompounds, and are antagonists of neuropeptide neurokinin-1 receptors(the “NK-1” receptor antagonists). “NK-1” receptor antagonists have beenshown to be useful therapeutic agents. For example, U.S. Pat. No.5,760,018 (1998) describes some “NK-1” receptor antagonists as useful inthe treatment of pain, inflammation, migraine and emesis (vomiting), andeach of U.S. Pat. No. 5,620,989 (1997), WO 95/19344 (1995), WO 94/13639(1994), and WO 94/10165 (1994) have described additional “NK-1” receptorantagonists which are useful in the treatment of treatment of pain,nociception and inflammation. Additional NK₁ receptor antagonists aredescribed in Wu et al, Tetrahedron 56, 3043-3051 (2000); Rombouts et al,Tetrahedron Letters 42, 7397-7399 (2001); and Rogiers et al,Tetrahedron, 57, 8971-8981 (2001). Among many compounds disclosed in theabovementioned '320 patent are several novel diazaspirodecan-2-ones,including the compound of Formula I, which is believed to be useful inthe treatment of nausea and emesis associated with chemotherapytreatments (Chemotherapy-induced nausea and emesis, CINE). Emesis hasbeen a problem in chemotherapy. Chemotherapeutic agents, for example,cisplatin carboplatin and temozolomide have been associated with bothacute and delayed onset nausea and vomiting. It is known to administerchemotherapeutic agents with an anti-emetic, for example, as describedin U.S. Pat. No. 5,939,098, which describes coadministration oftemozolomide and with ondansetron, however such therapy is not effectivein preventing delayed onset nausea and vomiting.

Compounds which have been identified as having therapeutic activity mustbe provided in a formulation suitable for administration to a patient inneed of the therapeutic properties of the compound. In general, dosageforms suitable for oral administration are preferred due to the ease ofadministration, negligible invasiveness of the administrative procedure,and the convenience of providing the medicament in a variety of discretedosage sizes. In general it is preferred to provide a solid oral dosageform which administers the therapeutic agent to a recipient through thegastrointestinal tract.

OBJECTIVES AND SUMMARY OF THE INVENTION

In view of the foregoing, what is desired is a solid orallyadministerable dosage form containing a salt of the compound of FormulaI. What is desired also is a dosage form that provides therapeuticallyeffective serum levels of the therapeutic agent and is robust towarddegradation under the environmental conditions in which it is handledand stored.

These and other objectives are provided by the present invention, whichin one aspect provides a granular pharmaceutical formulation comprisinga crystalline hydrochloride salt of the compound of Formula I inadmixture with one or more excipients, and optionally, one or more 5HT-3receptor antagonists, and optionally, a corticosteroid. When employed,preferably the 5HT-3 receptor antagonist is selected from Zofran(ondensetron), Kytril (granisetron), Aloxi (palonosetron), Anzemet(dolasetron), Navoban (tropisetron), and when employed, preferably thecorticosteroid is selected to be dexamethasone. In some preferredembodiments the granular composition comprises crystalline hydrochloridemonohydrate salt of(5S,8S)-8-[{(1R)-1-(3,5-Bis-(trifluoromethyl)phenyl)-ethoxy}-methyl]-8-phenyl-1,7-diazaspiro[4.5]decan-2-one,lactose monohydrate, microcrystalline cellulose, croscarmellose sodium,pregelatinized starch, and magnesium stearate. In some embodiments thegranular composition is contained in a gelatin capsule.

In some embodiments the pharmaceutical composition comprises a salt of(5S,8S)-8-[{(1R)-1-(3,5-Bis-(trifluoromethyl)phenyl)-ethoxy}-methyl]-8-phenyl-1,7-diazaspiro[4.5]decan-2-oneselected from a hydrochloride salt and a tosylate salt. In somepreferred embodiments the salt is a crystalline monohydratehydrochloride salt having characteristic X-ray Powder Diffraction peakspresent at a diffraction angle equal to those shown in Table I expressedin terms of 2θ (all values reflect an accuracy of ±0.2), with theassociated lattice “d” spacing (in angstroms) and relative peakintensities (“RI”):

TABLE I Diffraction angle Lattice Spacing (2θ, ± 0.2 RI (Å ± 0.04) 16.1Medium 5.49 18.4 Medium 4.83 21.6 Strong 4.11 23.5 Weak 3.78

Another aspect of the present invention is the provision of a solid oraldosage in capsule form comprising 2.5 mg/dose of a crystallinehydrochloride monohydrate salt form of(5S,8S)-8-[{(1R)-1-(3,5-Bis-(trifluoromethyl)phenyl)-ethoxy}-methyl]-8-phenyl-1,7-diazaspiro[4.5]decan-2-one(the hydrochloride monohydrate compound of Formula II),

having characteristic X-ray Powder Diffraction peaks present at adiffraction angle equal to those shown in Table II, expressed in termsof 2θ (all values reflect an accuracy of ±0.2), with the associatedlattice “d” spacing (in angstroms) and relative peak intensities (“RI”):

TABLE II Diffraction angle Lattice Spacing (2θ, ± 0.2 RI (Å ± 0.04) 16.1Medium 5.49 18.4 Medium 4.83 21.6 Strong 4.11 23.5 Weak  3.78;and having characteristic 12 sample average dissolution profile in 900mL of dissolution medium comprising 0.25% sodium lauryl sulfate solutionbuffered with 0.05 M sodium acetate at pH 4.5 determined using a USP 2Apparatus Paddle Stirrer with sinkers operated at 75 RPM of that shownin Table III.

TABLE III Time Average (% of active initially Range of % active released(min.) present released) over n samples  5 69% 64%-74%  15 88% 83%-94% 30 94% 90%-100% 45 97% 93%-102% 60 98% 94%-103%

Another aspect of the present invention is the provision of a solid oraldosage in capsule form comprising 10.0 mg/dose of a crystallinehydrochloride monohydrate salt form of(5S,8S)-8-[{(1R)-1-(3,5-Bis-(trifluoromethyl)phenyl)-ethoxy}-methyl]-8-phenyl-1,7-diazaspiro[4.5]decan-2-one(the hydrochloride monohydrate compound of Formula II)

having characteristic X-ray Powder Diffraction peaks present at adiffraction angle equal to those shown in Table IV, expressed in termsof 2θ (all values reflect an accuracy of ±0.2), with the associatedlattice “d” spacing (in angstroms) and relative peak intensities (“RI”):

TABLE IV Diffraction angle (2θ, ± 0.2 RI Lattice Spacing (Å ± 0.04) 16.1Medium 5.49 18.4 Medium 4.83 21.6 Strong 4.11 23.5 Weak 3.78and having a characteristic 12 sample average dissolution profile in 900mL of dissolution medium comprising 0.25% sodium lauryl sulfate solutionbuffered with 0.05 M sodium acetate at pH 4.5 determined using a USP 2Apparatus Paddle Stirrer with sinkers operated at 75 RPM of that shownin Table V.

TABLE V Time Average (% of active initially Range of % active released(min.) present released) over n samples  5 87% 82%-91%  15 95% 91%-98% 30 98% 94%-100% 45 98% 95%-101% 60 99% 96%-100%

Another aspect of the present invention is the provision of a solid oraldosage in capsule form comprising 50.0 mg/dose of a crystallinehydrochloride monohydrate salt form of(5S,8S)-8-[{(1R)-1-(3,5-Bis-(trifluoromethyl)phenyl)-ethoxy}-methyl]-8-phenyl-1,7-diazaspiro[4.5]decan-2-one(the hydrochloride monohydrate compound of Formula II)

having characteristic X-ray Powder Diffraction peaks present at adiffraction angle equal to those shown in Table VI, expressed in termsof 2θ (all values reflect an accuracy of ±0.2), with the associatedlattice “d” spacing (in angstroms) and relative peak intensities (“RI”):

TABLE VI Diffraction angle (2θ, ± 0.2 RI Lattice Spacing (Å ± 0.04) 16.1Medium 5.49 18.4 Medium 4.83 21.6 Strong 4.11 23.5 Weak 3.78having a characteristic 12 sample average dissolution profile in 900 mLof dissolution medium comprising 0.25% sodium lauryl sulfate solutionbuffered with 0.05 M sodium acetate at pH 4.5 determined using a USP 2Apparatus Paddle Stirrer with sinkers operated at 75 RPM of that shownin Table VII.

TABLE VII Time Average (% of active initially Range of % active released(min.) present released) over n samples  5  88% 74%-96%  15  97%91%-101% 30  99% 94%-102% 45 100% 95%-102% 60 100% 96%-103%

Another aspect of the present invention is the provision of apharmaceutical formulation comprising a hydrochloride monohydrate saltof Formula II in a capsule oral dosage form which has a Pharmacokinetic(PK) profile obtained under single dose rising rate study conditions inaccordance with Table VIII (average of eight study subjects).

TABLE VIII Dose Cmax* Half Life (mg) (ng/mL) Tmax** AUC*** T½ (hours) 527.3 2 931 not calc. 10 52.7 2.5 1820 not caic 25 119 2.5 17200 183 50276 3 33600 171 100 475 2 74400 181 200 944 4 148000 169 *Mean maximumplasma concentration following single administration. **Median time(hours) of maximum plasma concentration from administration. ***Areaunder the plasma concentration time curve in ng hr/mL for 0 to 72 hourspost administration.

The invention further provides a method of treating nausea and/oremesis. It is believed that medicament of the invention comprising saltsof the compound of Formula I may be useful in the provision ofanti-nausea and anti-emesis treatment for nausea and emesis arising fromany cause, for example, arising from chemotherapy, from radiationtherapy, arising during a post-operative recovery period, arising frommotion sickness, arising from morning sickness, and arising from innerear disturbances and infections. However, it is believed that thecompound of Formula I will be most effective in the provision ofanti-nausea and/or anti-emesis treatment for delayed onset nausea and/oremesis associated with chemotherapy treatments, radiation treatments,and arising during a post-operative period. In some embodiments it ispreferred to coadminister an NK-1 dosage form of the invention withother therapeutic agents, for example, a chemotherapeutic agent, forexample, temozolomide and cisplatin, preferably temozolomide. In someembodiments the administration of additional therapeutic agents isselected from contemporaneous administration of additional therapeuticagents contained in a separate dosage form and simultaneousadministration of a dosage form containing the granulate of the presentinvention along with one or more therapeutic agents.

An example of contemporaneous administration is administering before,during, or after administration of a medicament comprising the granulateof the present invention, one or more additional therapeutic agentscontained in one or more additional dosage forms. An example ofsimultaneous administration is a dosage form containing a medicamentcomprising multiple therapeutic agents. An example of the latteradministration scheme is a capsule dosage form containing the NK-1therapeutic agent together with one or more additional therapeuticagents, for example, a chemotherapeutic agent, for example,temozolomide. In some dosage forms containing more than one therapeuticagent it is preferred to prepare the formulation contained in the dosageform by introducing an admixture of all therapeutic agents into theformulation in place of the single drug substance, for example, the NK-1salt of the present formulation.

In one form the therapy comprises administering a particulate form of amedicament comprising crystalline hydrochloride monohydrate salt of(5S,8S)-8-[{(1R)-1-(3,5-Bis-(trifluoromethyl)phenyl)-ethoxy}-methyl]-8-phenyl-1,7-diazaspiro[4.5]decan-2-one(the monohydrate salt of Formula II), lactose monohydrate,microcrystalline cellulose, croscarmellose sodium, pregelatinizedstarch, and magnesium stearate in an amount providing a therapeuticallyeffective serum level of the hydrochloride monohydrate salt of FormulaII for the treatment and/or prevention of nausea and emesis. In theadministration of such particulate medicament, preferably theparticulate is contained in a capsule.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 presents a characteristic x-ray powder diffraction pattern of thecrystalline hydrochloride monohydrate salt form of the compound ofFormula I [Vertical Axis: Intensity CPS, counts (square root));Horizontal Axis: Two Theta (degrees)].

FIG. 2 presents a plasma concentration vs time profile following asingle dose administration of a medicament containing a hydrochloridesalt of the compound of Formula I administration to healthy humanvolunteers.

FIGS. 3A and 3B present a pharmacokinetic profile showing the plasmaconcentration vs time following a single day (Day 1; FIG. 3A) andmultiple day (Day 10; FIG. 3B) administration of a medicament containinga hydrochloride salt of the compound of Formula I to healthy humanvolunteers, horizontal axis is post administration time (hours),vertical axis is plasma concentration (ng/mL).

FIG. 4 presents the median and individual AUC values (area under thecurve from 0 to 72 hours post single dose administration), verticalaxis—AUC in ng hr/mL plasma, horizontal axis—single dose administered inmg of hydrochloride monohydrate salt of the compound of Formula I.

DETAILED DESCRIPTION OF THE INVENTION

The preparation of tachykinin compounds useful as NK-1 receptorantagonists has been described in U.S. Pat. No. 7,049,320, filed Dec.17, 2002 (herein, the '320 patent, which is incorporated herein byreference in its entirety), including(5S,8S)-8-[{(1R)-1-(3,5-Bis-(trifluoromethyl)phenyl)-ethoxy}-methyl]-8-phenyl-1,7-diazaspiro[4.5]decan-2-one(the compound of Formula I).

The preparation of salts of(5S,8S)-8-[{(1R)-1-(3,5-Bis-(trifluoromethyl)phenyl)-ethoxy}-methyl]-8-phenyl-1,7-diazaspiro[4.5]decan-2-one(the compound of Formula I), including the monohydrate hydrochloridesalt of Formula II (shown above) and various tosylate salts, havingphysical and chemical properties useful in the provision of medicamentsare disclosed in U.S. application Nos. 60/789,280 and 60/789,513, eachof which is incorporated herein in its entirety by reference.

Two of the most debilitating side effects of cytotoxic chemotherapy arenausea and vomiting (emesis). There is both acute-phase chemotherapyinduced nausea and emesis (CINE) and delayed-phase CINE. Acute-phaseCINE occurs in the first 24 hours after chemotherapy administrationwhile delayed-phase CINE manifests from between 2 days and 5 days postchemotherapy administration. Acute-phase CINE has been managed byadministering 5HT3 receptor antagonists, often in combination with acorticosteroid, for example, dexamethasone, this treatment has not beeneffective in managing delayed-phase CINE. It is believed thatacute-phase CINE and delayed-phase CINE arise from differentphysiological phenomena. It is believed that administration of an NK-1receptor antagonist, for example, salts of(5S,8S)-8-[{(1R)-1-(3,5-Bis-(trifluoromethyl)phenyl)-ethoxy}-methyl]-8-phenyl-1,7-diazaspiro[4.5]decan-2-one,either alone or in combination with one or more of a corticosteroid, forexample, dexamethasone and/or a 5HT3 receptor antagonist, for example,ondensetron, granisetron, palonosetron, dolasetron, or tropisetron willprovide a therapy effective in treatment of CINE in humans.

In general, oral dosage forms which administer a therapeutic agent to asubject through the gastrointestinal tract are desirable because suchdosage forms offer ease of administration with minimal invasion of thesubject receiving the therapy. Oral medicaments which are in a solidform, for example, tablets and capsules containing a particulatemedicament, offer a discrete dosage form of the medicament, and providethe medicament in a form which is generally more robust in theenvironment in which the medicament is handled and stored in comparisonto liquid dosage forms. Accordingly, it is desirable to providemedicaments containing these NK-1 receptor antagonists in a solid dosageform amenable to oral administration.

The inventors have discovered that a particulate containing a salt of(5S,8S)-8-[{(1R)-1-(3,5-Bis-(trifluoromethyl)phenyl)-ethoxy}-methyl]-8-phenyl-1,7-diazaspiro[4.5]decan-2-one(active salt) can be prepared which has useful pharmacokinetic (PK) anddissolution properties in the provision of therapy to address CINE andother conditions amenable to treatment by the administration of an NK-1inhibitor, for example, nausea and/or emesis due to other causativefactors, for example, motion sickness and morning sickness.Surprisingly, this particulate can be prepared by combining an amount ofthe active salt with lactose monohydrate, croscarmellose sodium, andpregelatinized starch and granulating the mixture with purified water,drying the granulate, blending the granulate with magnesium stearate andan additional amount of microcrystalline cellulose and croscarmellosesodium, and filling the resulting granulate blend into a gelatin capsuleat a fill weight that provides the dosage form with the desired amountof active salt. Surprisingly, the medicament of this formulationsuitably provides a serum therapeutic level of the active salt whenadministered orally. It is believed that this formulation, whenadministered in an effective dosage amount, and optionally, administeredalong with a separate medicament containing either a 5HT3 receptorantagonists, for example, ondensetron, granisetron, palonosetron,dolasetron, or tropisetron and/or one or more corticosteroid, forexample, dexamethasone, will be useful in the management of CINE.Optionally, the formulation of the invention can additionally includeone or more 5HT3 receptor antagonist, for example ondensetron,granisetron, palonosetron, dolasetron, or tropisetron, and/or one ormore corticosteroid, for example, dexamethasone, in the provision oftherapy in the treatment of both acute-phase and delayed-phase CINE.Whether administered as a separate medicament, or included in theformulation of the present invention, when utilized is it preferred forthe 5HT3 receptor antagonist to be selected from ondensetron,granisetron, palonosetron, dolasetron, and tropisetron, and whenutilized, whether as a separate medicament or included in theformulation of the present invention, it is preferred for thecorticosteroid to be selected from dexamethasone.

The present formulation can also contain additional therapeutic agents,for example, chemotherapeutic agents, for example, temozolomide,providing a single medicament for administering chemotherapeutictreatment and relief and/or prevention of nausea and/or vomitingassociated with such chemotherapeutic agent administration. Examples ofdosage levels of temozolomide are described in U.S. Pat. No. 5,939,098(the '098 patent), issued Aug. 17, 1999, European Patent 0858341 B1 (the'341 patent), Grant date Oct. 24, 2001, and published U.S. patentapplication no. 2006/0100188, published May 11, 2006 (the '188publication). Each of the '098 patent and '341 patent describescoadministration of temozolomide with a 5HT3 inhibitor to providetherapy for immediate onset nausea and vomiting associated withchemotherapy. The '188 publication, in Tables 1 and 2 (pages 2 to 3therein) describes detailed dosing regimens for dosing temozolomide. Insome embodiments it is preferred to provide a combination of a salt ofthe compound of Formula I prepared in accordance with the presentinvention, or a pharmaceutical composition containing the salt, andother therapeutic agents, for example, a chemotherapeutic agent, forexample, temozolomide and cisplatin, preferably temozolomide.

As used herein a combination includes: physically combined therapeuticagents in a pharmaceutical composition for administering in a singledosage form; a medicament or kit containing multiple therapeutic agentsin one or more containers; and providing therapy that includes providinga therapeutically effective level of the compound of Formula I and othertherapeutic agents, for example, by contemporaneous or simultaneousadministration, as described herein, of more than one therapeutic agent.When a kit combination is provided, generally multiple medicaments aresupplied in a form that will provide, upon administration to a patientin need of such therapy, a therapeutically effective amount of theactive pharmaceutical ingredient(s) contained therein.

It is believed also that this medicament may be useful in the treatmentof other conditions amenable to treatment by administration of an NK-1inhibitor, including, but not limited to, cough, morning sickness, andnausea and/or vomiting arising from motion sickness.

Preferably the active salt used in the formulations of the presentinvention is the crystalline hydrochloride monohydrate salt of(5S,8S)-8-[{(1R)-1-(3,5-Bis-(trifluoromethyl)phenyl)-ethoxy}-methyl]-8-phenyl-1,7-diazaspiro[4.5]decan-2-one,and a crystalline tosylate salt of(5S,8S)-8-[{(1R)-1-(3,5-Bis-(trifluoromethyl)phenyl)-ethoxy}-methyl]-8-phenyl-1,7-diazaspiro[4.5]decan-2-one,which salt has the X-ray powder diffraction pattern shown in FIG. 1.This salt has four most characteristic X-ray Powder Diffraction peakspresent at a diffraction angle equal to those shown in Table IX,expressed in terms of 2θ (all values reflect an accuracy of ±0.2), withthe associated lattice “d” spacing (in angstroms) and relative peakintensities (“RI”):

TABLE IX Diffraction angle (2θ, ± 0.2 RI Lattice Spacing (Å ± 0.04) 16.1Medium 5.49 18.4 Medium 4.83 21.6 Strong 4.11 23.5 Weak 3.78

In general, salts suitable for use in the formulation of the presentapplication may be prepared in accordance with the procedures describedin U.S. provisional application No. 60/789,280 entitled “HYDROCHLORIDESALTS OF8-[1-(3,5-Bis-(trifluoromethyl)phenyl)-ethoxymethyl]-8-phenyl-1,7-diazaspiro[4.5]decan-2-one”,filed on Apr. 5, 2006, and in U.S. patent application No. 11/732,548(now U.S. Patent No 8,178,550), filed on Apr. 4, 2007, each of which isincorporated herein by reference. Other suitable salts may be preparedin accordance with the procedures described in U.S. Provisionalapplication No. 60/789,513 entitled “SALTS OF8-[1-(3,5-Bis-(trifluoromethyl)phenylyethoxymethyl]-8-phenyl-1,7-diazaspiro[4.5]decan-2-oneAND PREPARATION PROCESS THEREFOR”, filed on Apr. 5, 2006, which isincorporated herein by reference. Particularly preferred is themonohydrate hydrochloride salt of(5S,8S)-8-[{(1R)-1-(3,5-Bis-(trifluoromethyl)phenyl)-ethoxy}-methyl]-8-phenyl-1,7-diazaspiro[4.5]decan-2-one,identified therein as the monohydrate hydrochloride form 1 salt of thecompound of Formula I, and depicted graphically above as the salt ofFormula II.

EXAMPLES

Standard pharmaceutical manufacturing processes are utilized in thepreparation of formulations of the present invention, including sieving,granulation, milling, fluid bed drying and powder mixing. Forpreparation of a granulate formula of the present invention theseoperations are carried out in accordance with the following generalprocedures. Blending operations are carried out in a high sheargranulator manufactured by Dionsa. Granulation is carried out in theDionsa granulator after the dry materials are blended to a homogeneousmixture. Wet milling is carried out in a Quadro Comil 197 equipped witha #5 mesh screen. Drying operations are carried out in a Strea AeromaticT2 Fluid Bed dryer. Dry milling operations are carried out in a QuadroComil 197 equipped with a 16 mesh screen. Blending operations arecarried out in a Pharmatech Double Cone blender.

Unless noted to the contrary, all materials utilized in the formulationswere articles of commerce meeting the current requirements of the UnitedStates Pharmacopeia/National Formulary (USP/NF), and active salts wereobtained using the procedures in the above described in the abovedescribed in U.S. Provisional Application Nos. 60/789,280 and 60/789,513filed concurrently on Apr. 5, 2006 which are incorporated herein byreference in their entirety, and U.S. Provisional Application No.60/919,666, filed on Mar. 22, 2007.

X-ray powder diffraction spectroscopic analysis of hydrochloridemonohydride salts was performed using a Rigaku Miniflex spectrometer,employing the following procedure. Specimens for analysis were lightlypacked onto a low-background plate. The specimens were exposed to theroom environment with ambient temperature and humidity. The Rigakuspectrometer was equipped with a six-plate carousel that rotated thespecimen at 54 rpm, minimizing preferred orientations of the crystals inthe sample studied. The Rigaku spectrometer was equipped also with acopper Ka radiation source utilized without a Kα2 filter. Thespectrometer was equipped also with a variable divergence slit and 0.3mm receiving slit. Scan range was carried out from 2.0 to 40° 2θ.Instrument calibration was verified using the Cu Kα1 peak for the 111plane. During scanning, the step size was 0.02 degrees over stepdurations of 0.6 seconds. Data analysis was accomplished using Jade Plus(release 5.0.26) analysis software. The data were smoothed with aSavitzky-Golay parabolic filter at 11 points. Typically reported “d”spacing values are accurate to within ±0.4 A.

Samples preparation analysis in accordance with the above-describedprocedure were subjected to minimal preparation to prevent any formchanges. Sample particles were lightly packed into the sample holder toinsure that they formed a smooth surface and did not clump together. Nosolvents, drying or other preparation steps were used for other than thesolvate samples prepared in accordance with the procedure describedabove.

Example I Granulate Formulation

The drug substance used in the following procedure was the hydrochloridemonohydrate salt of(5S,8S)-8-[{(1R)-1-(3,5-Bis-(trifluoromethyl)phenyl)-ethoxy}-methyl]-8-phenyl-1,7-diazaspiro[4.5]decan-2-one(herein, the hydrochloride monohydrate salt) has an X-ray powder patternshown in Figure I. The powder pattern of Figure I has four mostcharacteristic peaks observed at 2θ=16.1 (m), 18.4 (m), 21.6 (s), and23.5 (w)), produced in accordance with the above-referenced procedures.A granular formulation for filling into gelatin capsules containing thehydrochloride monohydrate salt for the provision of dosage formscontaining the salt in an amount of 2.5 mg/dose or 10 mg/dose and 50mg/dose was prepared in accordance with the following procedure. Theweight of each of the granulate constituents used is reported below inTable XIII, which varies slightly in the amount of filler employed foreach dosage strength of capsule produced from the granulate. Thegranulate was produced such that 300 mg of the powder provided theindicated amount of drug substance. The granulate for all dosagestrengths was prepared in accordance with the following procedure.

Drug substance was hand sieved through a 600 micron screen, and theremaining excipients were screened through a 1000 micron screen prior touse. The amount of drug substance indicated in Table XIII and the amountof lactose monohydrate (impalpable grade) indicated in Table XIII as“premix” were placed into the granulator and blended for 2 minutes at animpeller speed of 133 RPM to create a uniform blend. The amount oflactose monohydrate (impalpable grade) indicated in Table XIII as “mainmix”, the amount of croscarmellose sodium (NF Phr. Europe) indicated inTable XIII as intergranular, and the amount of starch indicated in TableXIII were added to the granulater and blended for 2 minutes at a 133 RPMimpeller speed. With the granulator operating, purified water was pumpedinto the dry-blended materials (up to 3600 ml at an addition rate of 75g/min) to agglomerate the blended materials until a granulate having 32wt. % water content was thereby formed. The wet granulate was wet-milledand sized using a conical screen mill equipped with a #5 mesh screen toprovide classified wet granulate. The classified wet granulate wastransferred into the fluid bed dryer and dried to a target weight ofless than 3 wt. % free water (determined by loss on drying). The driedgranulate was milled in the conical mill through a 16 mesh screen. Thedry-milled granulate is transferred to the blender along with the weightof croscarmellose sodium indicated in Table XIII as “extragranular”, andthe weight of microcrystalline cellulose (Avicel PH102) indicated inTable XIII. The constituents were blended for 20 minutes at 15 RPM. Theweight of magnesium stearate (Non-bovine, NF) indicated in Table XIIIwas screened through a 425 micron screen and added to the blender. Theconstituents were blended for 10 minutes at 15 RPM, and the blendedformulation was discharged for encapsulation.

As mentioned above, Table XIII, which follows, shows the weights of eachof the constituents used for preparing granulate which was used to fillcapsules in the indicated dosage range.

TABLE XIII Constituent 2.5 mg dosage 10 mg dosage 50 mg dosage ActiveSalt 100.0 g 400.0 g 1000.0 g Lactose Monohydrate 1600.0 g 1600.0 g1600.0 g (premix) Lactose Monohydrate 5560.0 g 5260.0 g 1030.0 g (mainmix) Microcrystalline Cellulose 2400.0 g 2400.0 g 1200.0 gPregelatinized Starch 1800.0 g 1800.0 g 900.0 g Croscarmellose Sodium240.0 g 240.0 g 120.0 g (intergranular) Croscarmellose Sodium 240.0 g240.0 g 120.0 g (extragranular) Magnesium Stearate 60.0 g 60.0 g 30.0 g

Samples of capsules filled with a granulate mixture that provides 2.5mg, 10 mg, and 50 mg of the active salt were subjected to dissolutiontests. The dissolution testing apparatus was a USP2 apparatus PaddleStirrer filled with 900 mL of dissolution medium consisting of 0.25%sodium lauryl sulfate solution buffered with 0.05 M sodium acetate at pH4.5. Tests were conducted at ambient temperature. The test was carriedout by stabilizing the dissolution medium at the test temperature withthe paddles set at 75 RPM. Test capsules are dropped into thedissolution medium with the paddles actuated. Periodically aliquotsamples of the dissolution media are withdrawn and analyzed by HPLC foractive content. The total amount of active present in the dissolutionmedia is calculated based on the HPLC determination, and reported as apercentage of the total amount of active contained in the capsuleintroduced into the dissolution media. The results for each sample areshown below in Table X. It will be found that capsules prepared inaccordance with the above-described procedure when tested under S-1conditions as a 6 tablet average with have a Q-45 of not less than 75%with no single tablet exceeding 80%.

TABLE X Time Average (% of active initially Range of % active released(min.) present released) over n samples 5  88% 74%-96%  15  97% 91%-101%30  99% 94%-102% 45 100% 95%-102% 60 100% 96%-103%

Single doses of the encapsulated formulation ranging from 5 mg of theactive salt (2×2.5 mg capsules) to 200 mg of active salt (4×50 mgcapsules) were administered to 6 cohorts each consisting of 10 healthyhuman volunteers, eight of whom were randomly selected to receive theactive drug and two of whom were randomly selected to receive placebo.Blood samples were collected from each volunteer at predose (hour 0) and0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72hours. The serum drug levels of the volunteers receiving active drug arepresent graphically in FIG. 2. The pharmacokinetic (PK) data from thisstudy is summarized in Table XI below.

TABLE XI Dose Cmax* Half Life (mg) (ng/mL) Tmax** AUG*** T½ (hours) 527.3 2 931 not calc. 10 52.7 2.5 1820 not calc 25 119 2.5 17200 183 50276 3 33600 171 100 475 2 74400 181 200 944 4 148000 169 *Mean maximumplasma concentration following single administration. **Median time(hours) of maximum plasma concentration from administration. ***Areaunder the plasma concentration time curve in nghr/mL for 0 to 72 hourspost administration.

FIG. 4 presents the AUC data graphically, both with respect toindividual data points (black circles) and statistical mean of the testgroup (line). These data indicate that the formulation provides theactive salt in a form that is rapidly absorbed and provides increasingexposure of the active in a dose-related manner.

In a second study, three cohorts of 8 healthy volunteers each wereadministered 10, 25, or 50 mg per day for each of 10 days.Administration in every case followed a 10 hour fast. Blood samples werecollected from each volunteer at predose (hour 0) and 0.25, 0.5, 0.75,1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours on each of days1 and 10. The results of this study are present graphically in FIGS. 3A(day 1) and 3B (day 10), and summarized in Table XII below.

TABLE XII Cmax* Half Life Dose (ng/mL) Tmax** AUC*** T½ (hours) Day 1Data 10 mg 48.6 3 673 not caic. 25 mg 139 2 1950 not caic 50 mg 254 33400 not caic Day 10 Data 10 mg 180 3 3590 238 25 mg 491 2 9720 notcalc. 50 mg 895 2.5 17700 172 *Mean maximum plasma concentrationfollowing single administration. **Median time (hours) of maximum plasmaconcentration from administration. ***Area under the plasmaconcentration time curve in ng · hr/mL for 0 to 72 hours postadministration.

These data show that the active is rapidly absorbed and that exposureincreases with increasing dose. The half-life is independent of dose andconsistent with that observed from the single dose studies. Accumulationis consistent with the long half life of the active and is approximately5-fold of the single dose.

What is claimed is:
 1. A method of treating nausea and/or emesis in a mammal comprising administering to the mammal a pharmaceutical formulation comprising a crystalline tosylate salt of (5S,8S)-8-[{(1R)-1-(3,5-bis-(trifluoromethyl)phenyl]-ethoxy}-methyl]-8-phenyl-1,7-diazaspiro[4,5]decan-2-one, and a pharmaceutically acceptable excipient, and wherein said nausea and/or emesis arises from chemotherapy, radiation therapy, motion sickness, morning sickness, or inner ear disturbances and infections, or wherein said nausea and/or emesis arises during a post-operative recovery period.
 2. The method according to claim 1 wherein the pharmaceutically acceptable excipient is selected from at least one of the group consisting of lactose, microcrystalline cellulose, croscarmellose sodium, pregelantinized starch, and magnesium stearate.
 3. The method of claim 1 wherein the formulation is a granular formulation.
 4. The method of claim 1 wherein the amount of active ingredient ranges from 5-200 mg per dosage form.
 5. The method of claim 1 wherein the dosage form contains 200 mg of the crystalline tosylate salt (5S,8S)-8-[{(1R)-I-(3,5-Bis-(trifluoromethyl)pheny]-ethoxy}-methyl]-8-phenyl-1,7-diazaspiro[4.5]decan-2-one. 